Gene-environment interaction is a seminal concept in the molecular epidemiology of human cancer. Our case-control (using hospital- and population-based controls) studies focus on lung cancer, a tobacco-related cancer. Exposure to second-hand tobacco smoke has many detrimental health effects, one of which is an increased lung cancer risk, and children may be more susceptible to the health hazards of second-hand smoke. Furthermore, alterations in the genetic background of innate immunity genes may further increase their susceptibility to lung cancer. Therefore, we hypothesized that never smokers, with specific mammose-binding lectin (MBL2) haplotypes predictive of high serum MBL levels, who are exposed to childhood second-hand smoke, may be more susceptible to developing lung cancer. We utilized the NCI-Maryland Lung Cancer Case-Control Study to investigate the association between childhood second-hand smoke and lung cancer risk. We found that the lung cancer among never smokers and among participants was associated with exposure to second-hand smoke during childhood. The MBL2 HYPA haplotype (high MBL secretor phenotype) was associated with lung cancer risk among those exposed to childhood second-hand smoke. These results were validated with an independent case-control study of never smokers from the Mayo Clinic. We also hypothesized that genetic variants in inflammation-related genes are associated with lung cancer survival. We analyzed 5 functional polymorphisms within MBL2 and the associated haplotypes and diplotypes from self-reported African-American and Caucasian patients in our ongoing NCI-Maryland Lung Cancer Case-Control Study and a case-only series from the greater Baltimore area. We found an association between the X allele of the promoter Y/X polymorphism (which results in a lower serum MBL concentration) and improved lung cancer survival restricted to Caucasians. A similar association was not seen among African Americans. When the levels of pack-years of smoking were divided into tertiles, the highest tertile was associated with improved lung cancer survival among Caucasians with the X, low serum allele, suggesting that high serum levels of MBL confer a worse prognosis among heavy smokers. The MBL2 LXA haplotype and XA/B diplotype, which are associated with low serum MBL levels, were associated with improved lung cancer survival among Caucasians. This is the first study to observe an association between functional polymorphisms in an innate immune system gene and lung cancer survival.